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EP3455208B1 - Composés des molecules petites de l'indole, et procédé pour leur utilisation. - Google Patents

Composés des molecules petites de l'indole, et procédé pour leur utilisation. Download PDF

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EP3455208B1
EP3455208B1 EP17724930.7A EP17724930A EP3455208B1 EP 3455208 B1 EP3455208 B1 EP 3455208B1 EP 17724930 A EP17724930 A EP 17724930A EP 3455208 B1 EP3455208 B1 EP 3455208B1
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substituted
unsubstituted
infection
compound
compounds
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EP3455208A1 (fr
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Xinbo Wang
Zhiping Lai
Yupeng PAN
Kuowei Huang
Zhigang Wang
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King Abdullah University of Science and Technology KAUST
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to Small Molecule N-(Alpha-Peroxy) Indole Compounds and Methods of Use
  • the background of this invention will address Malarial Infection, Resistance to Antimalarial Drugs and compounds.
  • Malaria is an infectious disease caused by mosquito-borne Plasmodium parasites affecting humans and other animals. The disease is prevalent in the tropical and subtropical regions of the world, particularly in areas around the equator. Malaria symptoms typically include chills, fever, fatigue, headaches, nausea or vomiting, and severe cases can result in seizures, coma, or death. More than 200 million cases of malaria occur worldwide annually resulting in over 500,000 deaths each year. The disease is most commonly transmitted by a bite from an infected Anopheles mosquito. The mosquito's saliva introduces the parasites into a person or animal's blood. Once in the bloodstream, the parasites travel to the liver where they mature and reproduce.
  • Plasmodium falciparum Malaria parasites belong to the genus Plasmodium (phylum Apicomplexa) and there are five known species of Plasmodium that can infect and be spread by humans. Plasmodium falciparum is the most common species identified in humans, followed by P. vivax. Less commonly isolated species are P. malariae, P. ovale, and P. knowlesi. P. falciparum generally accounts for the majority of deaths while P. vivax, P. ovale, and P. malariae usually causing a milder form of the disease.
  • Malaria infection develops via two phases: the first phase involves the liver, and the second phase involves the red blood cells.
  • the first phase involves the liver
  • the second phase involves the red blood cells.
  • the Plasmodium sporozoites from the mosquito's saliva enter the bloodstream, and migrate to the liver. Once the sporozoites infect the liver cells, they multiply over a period of 8-30 days, eventually causing the infected liver cells to rupture. The parasites then return to the bloodstream, where they infect the red blood cells.
  • the malaria parasite resides for most of its human life cycle within the liver and blood cells, it is somewhat unnoticed by immune surveillance, and is consequently protected from the body's immune system. However, circulating infected blood cells are destroyed in the spleen. In addition to this, the P. falciparum parasite secrete adhesive proteins on the surface of the infected red blood cells, causing the blood cells to adhere to the walls of small blood vessels, further sequestering the parasite from the general circulation and the spleen.
  • Diagnosis of malaria is made by microscopic examination of blood, or with antigen-based rapid diagnostic tests. Once diagnosed, the recommended treatment is a combination of antimalarial medications including chloroquine, quinine, mefloquine, amodiaquin, primaquine, pyrimethamine, sulfonamides, sulfones, dihydrofolate reductase inhibitors, and tetrandine, as well as others.
  • Antimalarial drugs such as cryptolepine and artemisinin
  • Cryptolepine and artemisinin are often initially effective; however, the parasites that cause the disease continuously evolve and become resistant to the drugs.
  • Resistance is now common against most classes of antimalarial drugs. Treatment of resistant strains has become progressively more reliant on a few remaining drugs, and continued use of these drugs will increase the incidence of resistance.
  • P. falciparum in particular has developed resistance to nearly all of the currently available antimalarial drugs.
  • many effective antimalarial drugs include an organic peroxide moiety, which generally includes two carbon atoms linked by the peroxide bond atoms.
  • the known methods for constructing the organic peroxide bond are highly inefficient and ineffective.
  • one method for constructing the organic peroxide moiety includes the coupling reaction of oxygen radicals to form a peroxide bond.
  • the oxygen free radicals are highly reactive, which makes unwanted side reactions difficult to control.
  • the known methods for constructing the organic peroxide moiety require either a special substrate (e.g., benzylic amine with N protected) or special conditions (e.g., heavy metal or hv ). Moreover, none of them can be integrated with the readily oxidizable indole residue and the classic peroxide oxidant to give N-( ⁇ -peroxy)indole, a somewhat rare structure that is present in active natural products.
  • CN-A-104 610 125 Wang et al., pub.
  • a class of N-( ⁇ -peroxy)indole compounds as described herein includes compounds of the following formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein A1, A2, A3, and A4 are each independently selected from CR and N, wherein each R is selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted
  • the compound has the following formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; and R 7 , R 5 , and R 9 are each independently selected from hydrogen, R
  • R 1 can be hydrogen.
  • R 2 can be hydrogen or alkoxy.
  • R 3 and/or R 4 can optionally be hydrogen.
  • R 5 can optionally be substituted or unsubstituted alkyl.
  • R 6 can optionally be hydrogen.
  • R 7 can be substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • R 8 can optionally be hydrogen.
  • R 9 can optionally be substituted or unsubstituted alkyl.
  • the compound has the following formula: or a pharmaceutically acceptable salt or prodrug thereof.
  • the N-( ⁇ -peroxy)indole compound is a compound selected from the group consisting of: and
  • the compound has the following formula: or a pharmaceutically acceptable salt or prodrug thereof, wherein R 10 , R 11 , R 12 , R 13 , and R 14 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • the compound can optionally be selected from the group consisting of
  • compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.
  • a method of treating a parasitic infection in a subject comprises administering to a subject an effective amount of a compound or a composition as described herein.
  • the parasitic infection is a Plasmodium infection (e.g., a Plasmodium falciparum infection).
  • the parasitic infection is malaria.
  • the methods can further comprise administering to the subject an additional therapeutic agent (e.g., an anti-malarial agent).
  • a method of treating a bacterial infection in a subject comprises administering to a subject an effective amount of a compound or a composition as described herein.
  • the methods can further comprise administering to the subject an additional therapeutic agent (e.g., an antibacterial agent).
  • a method of treating cancer in a subject comprises administering to a subject an effective amount of a compound or a composition as described herein.
  • the methods can further comprise administering to the subject an additional therapeutic agent (e.g., an anti- cancer agent).
  • N-( ⁇ -peroxy)indole compounds and methods for their use.
  • the N- (a-peroxy)indole compounds described herein are useful for treating parasitic infections, bacterial infections, and cancer in subjects.
  • the methods include administering an N-( ⁇ -peroxy)indole compound as described herein to a subject.
  • a class of N-( ⁇ -peroxy)indole compounds described herein is represented by Formula I: and pharmaceutically acceptable salts and prodrugs thereof.
  • a 1 , A 2 , A 3 , and A 4 are each independently selected from CR and N.
  • Each R is selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • R 7 , R 8 , and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • adjacent R groups can be combined to form a cyclic compound, e.g., a substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkenyl.
  • R 5 and R 6 do not combine to form a cyclic compound.
  • A1, A2, A3, and A4 are each independently selected from CR
  • Formula I can be represented by Structure I-A:
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • R 1 is hydrogen.
  • R 2 is hydrogen or alkoxy.
  • R 3 is hydrogen.
  • R 4 is hydrogen.
  • R 7 , R 8 , and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • R 7 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl.
  • R 8 can optionally be hydrogen.
  • R 9 can optionally be substituted or unsubstituted alkyl.
  • R 7 is isobutyl and R 8 is hydrogen.
  • Formula I can be represented by Structure 1-B:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 are as described above for Structure I-A.
  • Examples of Structure 1-B include the following compounds:
  • R 7 is substituted or unsubstituted aryl and R 8 is hydrogen.
  • Examples include the following compounds:
  • alkyl, alkenyl, and alkynyl include straight- and branched-chain monovalent substituents. Examples include methyl, ethyl, isobutyl, 3-butynyl, and the like. Ranges of these groups useful with the compounds and methods described herein include C 1 -C 20 alkyl, C 2 -C 20 alkenyl, and C 2 -C 20 alkynyl.
  • Additional ranges of these groups useful with the compounds and methods described herein include C 1 -C 2 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl.
  • Heteroalkyl, heteroalkenyl, and heteroalkynyl are defined similarly as alkyl, alkenyl, and alkynyl, but can contain O, S, or N heteroatoms or combinations thereof within the backbone. Ranges of these groups useful with the compounds and methods described herein include C 1 -C 20 heteroalkyl, C 2 -C 20 heteroalkenyl, and C 2 -C 20 heteroalkynyl.
  • Ci-C 12 heteroalkyl C 2 - C 12 heteroalkenyl, C 2 -C 12 heteroalkynyl, C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 2 -C 6 heteroalkynyl, C 1 -C 4 heteroalkyl, C 2 -C 4 heteroalkenyl, and C 2 -C 4 heteroalkynyl.
  • cycloalkyl, cycloalkenyl, and cycloalkynyl include cyclic alkyl groups having a single cyclic ring or multiple condensed rings. Examples include cyclohexyl, cyclopentylethyl, and adamantanyl. Ranges of these groups useful with the compounds and methods described herein include C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, and C 3 -C 20 cycloalkynyl.
  • Additional ranges of these groups useful with the compounds and methods described herein include C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, C 5 -C 12 cycloalkynyl, C 5 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, and C 5 -C 6 cycloalkynyl.
  • heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl are defined similarly as cycloalkyl, cycloalkenyl, and cycloalkynyl, but can contain O, S, or N heteroatoms or combinations thereof within the cyclic backbone. Ranges of these groups useful with the compounds and methods described herein include C 3 -C 20 heterocycloalkyl, C 3 -C 20 heterocycloalkenyl, and C 3 -C 20 heterocycloalkynyl.
  • Additional ranges of these groups useful with the compounds and methods described herein include C 5 -C 12 heterocycloalkyl, C 5 -C 12 heterocycloalkenyl, C 5 -C 12 heterocycloalkynyl, C 5 -C 6 heterocycloalkyl, C 5 -C 6 heterocycloalkenyl, and C 5 -C 6 heterocycloalkynyl.
  • Aryl molecules include, for example, cyclic hydrocarbons that incorporate one or more planar sets of, typically, six carbon atoms that are connected by delocalized electrons numbering the same as if they consisted of alternating single and double covalent bonds.
  • An example of an aryl molecule is benzene.
  • Heteroaryl molecules include substitutions along their main cyclic chain of atoms such as O, N, or S. When heteroatoms are introduced, a set of five atoms, e.g., four carbon and a heteroatom, can create an aromatic system. Examples of heteroaryl molecules include furan, pyrrole, thiophene, imadazole, oxazole, pyridine, and pyrazine.
  • Aryl and heteroaryl molecules can also include additional fused rings, for example, benzofuran, indole, benzothiophene, naphthalene, anthracene, and quinoline.
  • the aryl and heteroaryl molecules can be attached at any position on the ring, unless otherwise noted.
  • alkoxy as used herein is an alkyl group bound through a single, terminal ether linkage.
  • aryloxy as used herein is an aryl group bound through a single, terminal ether linkage.
  • alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy, heteroalkynyloxy, heteroaryloxy, cycloalkyloxy, and heterocycloalkyloxy as used herein are an alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy, heteroalkynyloxy, heteroaryloxy, cycloalkyloxy, and heterocycloalkyloxy group, respectively, bound through a single, terminal ether linkage.
  • hydroxy as used herein is represented by the formula -OH .
  • amine or amino as used herein are represented by the formula-NZ 1 Z 2 , where Z 1 and Z 2 can each be substitution group as described herein, such as hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, or heterocycloalkyl molecules used herein can be substituted or unsubstituted.
  • the term substituted includes the addition of an alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, or heterocycloalkyl group to a position attached to the main chain of the alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, or heterocycloalkyl, e.g., the replacement of a hydrogen by one of these molecules.
  • substitution groups include, but are not limited to, hydroxy, halogen (e.g., F, Br, Cl, or I), and carboxyl groups.
  • halogen e.g., F, Br, Cl, or I
  • carboxyl groups examples include, but are not limited to, hydroxy, halogen (e.g., F, Br, Cl, or I), and carboxyl groups.
  • the term unsubstituted indicates the alkoxy, aryloxy, amino, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, or heterocycloalkyl has a full complement of hydrogens, i.e., commensurate with its saturation level, with no substitutions, e.g., linear decane (-(CH 2 ) 9 -CH 3 ).
  • the compounds described herein can be prepared in a variety of ways.
  • the compounds can be synthesized using various synthetic methods. At least some of these methods include synthetic organic chemistry.
  • the compounds described herein can be prepared from readily available starting materials. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by optimization procedures.
  • Variations on Formula I include the addition, subtraction, or movement of the various constituents as described for each compound. Similarly, when one or more chiral centers are present in a molecule, all possible chiral variants are included. Additionally, compound synthesis can involve the protection and deprotection of various chemical groups. The use of protection and deprotection, and the selection of appropriate protecting groups can be determined. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, 2002 .
  • Reactions to produce the compounds described herein can be carried out in solvents, which can be selected for organic synthesis.
  • Solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products under the conditions at which the reactions are carried out, i.e., temperature and pressure.
  • Reactions can be carried out in one solvent or a mixture of more than one solvent.
  • Product or intermediate formation can be monitored; for example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatography
  • N-( ⁇ -peroxy)indole compounds described herein can be prepared according to Scheme 1 shown below.
  • an indole or indole derivative, a carbonyl compound, and a peroxide are reacted in the presence of a catalyst.
  • the indole derivative can be, for example, an indoline compound (e.g., 3-methyl-indoline) or amino-protected histidine esters.
  • the carbonyl compound is an aldehyde, including aliphatic aldehydes or aromatic aldehydes, such as isoamyl aldehyde and benzaldehyde.
  • the carbonyl compound is a ketone.
  • the peroxide can be a hydroperoxide or a protected peroxide, such as a trimethylsilyl (TMS)-protected peroxide.
  • TMS trimethylsilyl
  • the ratio of indole to carbonyl to peroxide can optionally be 1 part indole to 2 parts carbonyl to 3 parts peroxide.
  • the catalyst can be an acid catalyst, such as p -toluenesulfonic acid (PTSA).
  • PTSA p -toluenesulfonic acid
  • the reaction can be performed in the presence of a solvent. Suitable solvents include, for example, halogenated solvents, such as dichloromethane, dichloroethane, and chloroform, and other aprotic solvents.
  • the reaction can be performed for a period of time.
  • the reaction can be performed for a period up to 24 hours (e.g., 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours, inclusive).
  • Example 1 Exemplary methods for synthesizing the compounds as described herein are provided in Example 1 below.
  • the compounds described herein can be provided in a pharmaceutical composition.
  • the pharmaceutical composition can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, or suspensions, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include a therapeutically effective amount of the compound described herein in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, or diluents.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, which can be administered to an individual along with the selected compound without causing unacceptable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained.
  • the term carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other materials for use in pharmaceutical formulations.
  • a carrier for use in a composition will depend upon the intended route of administration for the composition.
  • the preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington: The Science and Practice of Pharmacy, 22d Edition, Loyd et al. eds., Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences (2012 ).
  • physiologically acceptable carriers include buffers, such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/or nonionic surfactants, such as TWEEN® (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICSTM (BASF; Florham Park, NJ).
  • buffers such as phosphate buffers, citrate buffer, and buffer
  • compositions containing the compound described herein suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants, such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be promoted by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • Isotonic agents for example, sugars, sodium chloride, and the like may also be included.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration of the compounds described herein include capsules, tablets, pills, powders, and granules.
  • the compounds described herein is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary am
  • compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings. They may contain opacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration of the compounds described herein include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents, such as water or other solvents, solubilizing agents, and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents such as water or other solvents, solubilizing agents, and
  • the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.
  • Suspensions in addition to the active compounds, may contain additional agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions of the compounds described herein for rectal administrations are optionally suppositories, whichcan beprepared by mixing the compounds with suitable nonirritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of the compounds described herein include ointments, powders, sprays, and inhalants.
  • the compounds described herein are admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, ointments, powders, and solutions are also contemplated as being within the scope of the compositions.
  • compositions can include one or more of the compounds described herein and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable salt refers to those salts of the compound described herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds described herein.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds described herein.
  • salts can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, methane sulphonate, and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Administration of the compounds and compositions described herein or pharmaceutically acceptable salts thereof can be carried out using therapeutically effective amounts of the compounds and compositions described herein orpharmaceutically acceptable salts thereof as described herein for periods of time effective to treat a disorder.
  • the effective amount of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein may be determined and includes exemplary dosage amounts for a mammal of from about 0.5 to about 200 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day.
  • the dosage amount can be from about 0.5 to about 150 mg/kg of body weight of active compound per day, about 0.5 to 100 mg/kg of body weight of active compound per day, about 0.5 to about 75 mg/kg of body weight of active compound per day, about 0.5 to about 50 mg/kg of body weight of active compound per day, about 0.01 to about 50 mg/kg of body weight of active compound per day, about 0.05 to about 25 mg/kg of body weight of active compound per day, about 0.1 to about 25 mg/kg of body weight of active compound per day, about 0.5 to about 25 mg/kg of body weight of active compound per day, about 1 to about 20 mg/kg of body weight of active compound per day, about 1 to about 10 mg/kg of body weight of active compound per day, about 20 mg/kg of body weight of active compound per day, about 10 mg/kg of body weight of active compound per day, about 5 mg/kg of body weight of active compound per day, about 2.5 mg/kg of body weight of active compound per day, about 1.0 mg/kg of body weight of active compound per day,
  • the dosage amounts are from about 0.01 mg/kg to about 10 mg/kg ofbody weight of active compound per day.
  • the dosage amount is from about 0.01 mg/kg to about 5 mg/kg.
  • the dosage amount is from about 0.01 mg/kg to about 2.5 mg/kg.
  • the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
  • the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject's circumstances. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. Further, the route of administration would assist in determination of doses that result in a plasma concentration for a desired level of response in the cells, tissues and/or organs of a subject.
  • the methods include administering to a subject an effective amount of one or more of the compounds or compositions described herein or a pharmaceutically acceptable salt or prodrug thereof.
  • the method can include selecting a subject with a parasitic infection, a bacterial infection, or cancer.
  • the expression "effective amount,” when used to describe an amount of compound in a method, refers to the amount of a compound that achieves the desired pharmacological effect or other effect, for example, an amount that results in infection reduction or tumor growth rate reduction.
  • the compounds and compositions described herein or pharmaceutically acceptable salts thereof are useful for treating parasitic infections, bacterial infections, and/or cancer in humans, including, without limitation, pediatric and geriatric populations, and in animals, e.g., veterinary applications.
  • the parasitic infection is a Plasmodium infection, such as a Plasmodium falciparum infection.
  • the parasitic infection is malaria.
  • the parasitic infection is a Toxoplarma gondii infection, a Leishmania infection, or a Babesia infection.
  • the bacterial infection is a Gram-negative bacterial infection, such as an Acinetobacter infection (e.g., an Acinetobacter baumannii infection), a Pseudomonas infection (e.g., a Pseudomonas aeruginosa infection), a Klebsiella infection, an Escherichia infection, a Salmonella infection, a Yersinia infection, a Shigella infection, a Proteus infection, an Enterobacter infection, a Serratia infection, or a Citrobacter infection.
  • Acinetobacter infection e.g., an Acinetobacter baumannii infection
  • a Pseudomonas infection e.g., a Pseudomonas aeruginosa infection
  • Klebsiella infection e.g., an Escherichia infection
  • a Salmonella infection e.g., a Salmonella infection
  • Yersinia infection e.
  • the microbial infection is a Gram-positive bacterial infection, such as a Bacillus infection, a Listeria infection, a Staphylococcus infection, a Streptococcus infection, an Enterococcus infection, or a Clostridium infection.
  • a Gram-positive bacterial infection such as a Bacillus infection, a Listeria infection, a Staphylococcus infection, a Streptococcus infection, an Enterococcus infection, or a Clostridium infection.
  • the cancer is bladder cancer, brain cancer, breast cancer, colorectal cancer (e.g., colon cancer, rectal cancer), cervical cancer, chondrosarcoma, endometrial cancer, gastrointestinal cancer, gastric cancer, genitourinary cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, or testicular cancer.
  • colorectal cancer e.g., colon cancer, rectal cancer
  • cervical cancer e.g., chondrosarcoma
  • endometrial cancer e.g., gastrointestinal cancer, gastric cancer, genitourinary cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, or testicular cancer.
  • the method of treating parasitic infections, bacterial infections, and/or cancer in a subject can further comprise administering to the subject one or more additional therapeutic agents.
  • the one or more additional agents and the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof can be administered in any order, including concomitant, simultaneous, or sequential administration. Sequential administration can be temporally spaced order of up to several days apart.
  • the methods can also include more than a single administration of the one or more additional agents and/or the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof.
  • the administration of the one or more additional agents and the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof can be by the same or different routes and concurrently or sequentially.
  • Therapeutic agents include, but are not limited to, antimalarial agents.
  • An antimalarial agent is a compound or composition effective in inhibiting or arresting the activity of a Plasmodium parasite.
  • Suitable antimalarial agents include, for example, chloroquine, quinine, mefloquine, amodiaquin, primaquine, pyrimethamine, sulfonamides, sulfones, dihydrofolate reductase inhibitors, and tetrandine.
  • Antibacterial agents can also be used as the therapeutic agents.
  • Suitable antibacterial agents can include any agent effective for treating a bacterial infection and include, for example, tetracyclines (e.g., minocycline), quinolones (e.g., ciprofloxacin, levofloxacin, and nalidixic acid), aminoglycosides (e.g., amikacin, gentamycin, kanamycin, and tobramycin), carbapenems (e.g., meropenem), cephalosporins (e.g., ceftriaxone), macrolides (e.g., erythromycin), polypeptides (e.g., colistin and polymxin B), sulfonamides (e.g., sulfamethoxazole), glycylcyclines (e.g., tigecycline), beta lactams (e.g., penams), lipopeptide
  • Therapeutic agents further include, but are not limited to, chemotherapeutic agents.
  • a chemotherapeutic agent is a compound or composition effective in inhibiting or arresting the growth of an abnormally growing cell. Thus, such an agent may be used therapeutically to treat cancer as well as other diseases marked by abnormal cell growth.
  • chemotherapeutic compounds include, but are not limited to, bexarotene, gefitinib, erlotinib, gemcitabine, paclitaxel, docetaxel, topotecan, irinotecan, temozolomide, carmustine, vinorelbine, capecitabine, leucovorin, oxaliplatin, bevacizumab, cetuximab, panitumumab, bortezomib, oblimersen, hexamethylmelamine, ifosfamide, CPT-11, deflunomide, cycloheximide, dicarbazine, asparaginase, mitotant, vinblastine sulfate, carboplatin, colchicine, etoposide, melphalan, 6-mercaptopurine, teniposide, vinblastine, antibiotic derivatives (e.g.
  • anthracyclines such as doxorubicin, liposomal doxorubicin, and diethylstilbestrol doxorubicin, bleomycin, daunorubicin, and dactinomycin
  • antiestrogens e.g., tamoxifen
  • antimetabolites e.g., fluorouracil (FU), 5-FU, methotrexate, floxuridine, interferon alpha-2B, glutamic acid, plicamycin, mercaptopurine, and 6-thioguanine
  • cytotoxic agents e.g., carmustine, BCNU, lomustine, CCNU, cytosine arabinoside, cyclophosphamide, estramustine, hydroxyurea, procarbazine, mitomycin, busulfan, cisplatin, vincristine and vincristine sulfate
  • hormones e.g., medroxyprogesterone, estram
  • a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein are administered to a subject prior to onset (e.g., before obvious signs of a parasitic infection, a bacterial infection, or cancer), during early onset (e.g., upon initial signs and symptoms of a parasitic infection, a bacterial infection, or cancer), or after the development of a parasitic infection, a bacterial infection, or cancer.
  • Prophylactic administration can occur for several days to years prior to the manifestation of symptoms of a parasitic infection, a bacterial infection, or cancer.
  • Therapeutic treatment involves administering to a subject a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein after a parasitic infection, a bacterial infection, or cancer is diagnosed.
  • treatment refers to a method of reducing one or more symptoms of an infection, disease, or condition.
  • treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of one or more symptoms of the infection, disease, or condition.
  • a method for treating an infection, disease, or condition is considered to be a treatment if there is a 10% reduction in one or more symptoms or signs of the infection, disease, or condition in a subject as compared to a control.
  • control refers to the untreated infection, disease, or condition.
  • the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the infection, disease, condition, or symptoms of the infection, disease or condition.
  • references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level. Such terms can include, but do not necessarily include, complete elimination.
  • subject means both mammals and non-mammals.
  • Mammals include, for example, humans; non-human primates, e.g., apes and monkeys; cattle; horses; sheep; rats; mice; pigs; and goats.
  • Non-mammals include, for example, fish and birds.

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Claims (13)

  1. Composition comprenant un composé de formule suivante :
    Figure imgb0060
     ou un sel pharmaceutiquement acceptable d'un tel composé, formule dans laquelle :
    chacun de A1, A2, A3 et A4 est indépendamment choisi parmi CR et N, où chaque R est choisi dans l'ensemble constitué par un hydrogène, halogène, cyano, trifluorométhyle, alcoxy, aryloxy, carbonyle substitué ou non substitué, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, hétéroalcényle substitué ou non substitué, hétéroalcynyle substitué ou non substitué, aryle substitué ou non substitué, hétéroaryle substitué ou non substitué, cycloalkyle substitué ou non substitué, et hétérocycloalkyle substitué ou non substitué ;
    chacun de R5 et R6 est indépendamment choisi parmi un hydrogène, halogène, cyano, trifluorométhyle, alcoxy, aryloxy, carbonyle substitué ou non substitué, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, hétéroalcényle substitué ou non substitué, hétéroalcynyle substitué ou non substitué, aryle substitué ou non substitué, hétéroaryle substitué ou non substitué, cycloalkyle substitué ou non substitué, et hétérocycloalkyle substitué ou non substitué ; et
    chacun de R7, R8 et R9 est indépendamment choisi parmi un hydrogène, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, hétéroalcényle substitué ou non substitué, hétéroalcynyle substitué ou non substitué, aryle substitué ou non substitué, hétéroaryle substitué ou non substitué, cycloalkyle substitué ou non substitué, et hétérocycloalkyle substitué ou non substitué,
    dans laquelle R5 et R6 ne se combinent pas pour former un composé cyclique ;
    et un véhicule pharmaceutiquement acceptable.
  2. Composition selon la revendication 1, dans laquelle le composé répond à la formule :
    Figure imgb0061
     ou est un sel pharmaceutiquement acceptable d'un tel composé, formule dans laquelle :
    chacun de R1, R2, R3, R4, R5 et R6 est indépendamment choisi parmi un hydrogène, halogène, cyano, trifluorométhyle, alcoxy, aryloxy, carbonyle substitué ou non substitué, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, hétéroalcényle substitué ou non substitué, hétéroalcynyle substitué ou non substitué, aryle substitué ou non substitué, hétéroaryle substitué ou non substitué, cycloalkyle substitué ou non substitué, et hétérocycloalkyle substitué ou non substitué ; et
    chacun de R7, R8 et R9 est indépendamment choisi parmi un hydrogène, alkyle substitué ou non substitué, alcényle substitué ou non substitué, alcynyle substitué ou non substitué, hétéroalkyle substitué ou non substitué, hétéroalcényle substitué ou non substitué, hétéroalcynyle substitué ou non substitué, aryle substitué ou non substitué, hétéroaryle substitué ou non substitué, cycloalkyle substitué ou non substitué, et hétérocycloalkyle substitué ou non substitué ;
    dans laquelle R5 et R6 ne se combinent pas pour former un composé cyclique ;
  3. Composition selon la revendication 2, dans laquelle au moins l'un parmi R1, R3, R4, R6 et R8 est un hydrogène.
  4. Composition selon la revendication 2 ou 3, dans laquelle R2 est un hydrogène ou alcoxy.
  5. Composition selon l'une quelconque des revendications 2 à 4, dans laquelle R5 ou R9 ou R7 est un alkyle substitué ou non substitué.
  6. Composition selon l'une quelconque des revendications 2 à 5, dans laquelle R7 est un aryle substitué ou non substitué.
  7. Composition selon la revendication 2, dans laquelle le composé de formule (II) est défini par la structure suivante :
    Figure imgb0062
  8. Composition selon la revendication 7, dans laquelle le composé est choisi dans l'ensemble constitué par :
    Figure imgb0063
    Figure imgb0064
     et
    Figure imgb0065
    Figure imgb0066
  9. Composition selon la revendication 2, dans laquelle le composé est choisi dans l'ensemble constitué par :
    Figure imgb0067
  10. Composition selon la revendication 8 ou 9, pour une utilisation dans le traitement d'une infection bactérienne, d'une infection parasitaire, ou d'un cancer.
  11. Composition pour une utilisation selon la revendication 10, dans laquelle l'infection parasitaire est une infection par Plasmodium ou le paludisme, et dans laquelle l'infection par Plasmodium est une infection par Plasmodium falciparum.
  12. Composé N-(α-peroxy)indole, ou un sel pharmaceutiquement acceptable de celui-ci, pour une utilisation dans le traitement d'une infection bactérienne, d'une infection parasitaire, ou d'un cancer, lequel composé N-(α-peroxy)indole est choisi dans l'ensemble constitué par :
    Figure imgb0068
    Figure imgb0069
    Figure imgb0070
     et
    Figure imgb0071
     ou
    Figure imgb0072
  13. Composé pour une utilisation selon la revendication 12, dans lequel l'infection parasitaire est une infection par Plasmodium ou le paludisme, et dans lequel l'infection par Plasmodium est une infection par Plasmodium falciparum.
EP17724930.7A 2016-05-11 2017-05-10 Composés des molecules petites de l'indole, et procédé pour leur utilisation. Not-in-force EP3455208B1 (fr)

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